The present invention relates to pharmaceuticals and, more particularly, it relates to 4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepine derivatives or salts thereof and also to a drug composition containing the same and a pharmaceutically acceptable carrier.
Oxytocin is a peptide hormone which is mainly synthesized in hypothalamus and is secreted after an axonal transport in nerve cells to posterior pituitarity. It has been known already that an extract from posterior pituitarity has an activity of uterus contraction and of milk secretion, and two years after the elucidation of its amino acid structure in 1953, clinical application of synthetic oxytoxin started. As such, clinical application firstly proceeded for oxytocin, and it was used as a drug for controlling labor pains while analysis of physiological mechanism of oxytocin has not made so much progress. As the reasons therefor, it can be considered that since oxytocin is a small amino acid peptide, measurement of its concentration in blood was difficult, blood and tissues contain large amounts of oxytocin decomposition enzymes and that analysis of oxytocin receptor was difficult (cf. Sanka to Fujinka, 10: 59-65, 1995).
It has been recently clarified that besides the above-mentioned two classic physiological actions, oxytocin has various physiological actions in addition to the area of delivery such as central action for maternal behavior and for memory, action to functional regulation of sexual glands, action as a neurotransmitter, and action in immune system (Kusuri no Kaisetsu, Vol. 30, No. 10: 1164-1167, 1994). Oxytocin receptor was cloned, too (Kimura, T. et al., Nature, 356: 526-529, 1992), and it is now possible to investigate the expression of the receptor in terms of molecular biology. It has been known that oxytocin receptor is mostly expressed in uterine muscle and endometrium in the cases of labor pain onset in term delivery.
Since the above-mentioned expression of oxytocin receptor in uterine muscle and endometrium increases in the cases of early delivery, the effect as a suppressor for uterine contraction at early delivery can be expected, and accordingly, investigation for oxytocin antagonist has started. As a drug which is the first runner in the clinical application, atosiban which is a peptidal oxytocin antagonist is available at present, and there is a report on the cases where it significantly lowers the frequency of uterine contraction without changes in heart rate and blood pressure during that time (Goodwin, T. M. et al., Am. J. Obstet. Gynecol., 170: 474-478, 1994). It has been ascertained that atosiban has an antagonistic action not only to oxytocin receptor but also to vasopressin V1 receptor.
Incidentally, oxytocin antagonists are mentioned in European Patent No. 450,761A and in Unexamined Published Japanese Patent Application No. 5-213,865. In addition, benzoheterocyclic derivatives represented by the following formula are mentioned in WO95/34540, and with respect to their vasopressin-acting/antagonizing action, specific pharmacological test methods, and the test results are mentioned therein. However, so far as an oxytocin-antagonizing action of these compounds is concerned, it is mentioned quite briefly only in one line, and any specific pharmacological test method and test results thereof are not disclosed at all: 
R2 is a hydrogen atom, . . . (omitted) . . . ; R3 is a hydrogen atom, . . . (omitted) . . . ; or R2 and R3 are taken together to form an oxo group, a lower alkylidene group, a lower alkoxy-substituted lower alkylidene group, a lower alkoxycarbonyl-substituted lower alkylidene group, or a phenyl-substituted lower alkylidene group; X is a methylene group, a simple linkage, or a group represented by the formula, xe2x95x90CHxe2x80x94 or NR14; and for others, refer to the above-cited patent specifications.)
We, the present inventors conducted intensive studies for finding compounds having an antagonistic action to oxytocin. As a result, it has been found that novel 4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepine derivatives have a strong oxytoxin-antagonizing action, whereupon the present invention has been achieved.
Thus, the present invention relates to 4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepine derivatives or salts thereof having oxytoxin antagonism, as represented by the following formula (I). The present invention also relates to a drug composition, particularly an oxytocin antagonist, containing the 4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepine derivative or its salt and a drug acceptable carrier: 
(In the formula, each of the symbols has the following meaning:
ring A: a 5-membered heteroarylene group;
ring B: an optionally substituted aryl group or a 5- to 6-membered heteroaryl group;
D: a carbonyl group or a lower alkylene group;
R1: a group represented by formula, NR3R4, an xe2x80x94O-lower alkyl group, or OH;
R2: an optionally halogen atom-substituted lower alkyl group, an xe2x80x94O-lower alkyl group, an xe2x80x94S-lower alkyl group, or a xe2x80x94CO-lower alkyl group;
R3, R4: same or different and each is
1) a hydrogen atom,
2) a lower alkyl group (the lower alkyl group may be substituted with OH, an optionally protected amino group, an optionally protected mono-lower alkylamino group, a di-lower alkylamino group, an optionally lower alkyl group-substituted 5- to 7-membered saturated heterocyclic group, a 5- to 6-membered heteroaryl group, or an aryl group),
3) a cycloalkyl group,
4) an optionally lower alkyl group-substituted 5- to 7-membered saturated heterocyclic group,
5) a 5- to 6-membered heteroaryl group,
6) an aryl group, or
7) an optionally substituted 5- to 7-membered nitrogen-containing heterocyclic group formed by integration of the formula, NR3R4 (the 5- to 7-membered nitrogen-containing heterocyclic group may be fused with a benzene ring or with a 5- to 6-membered heteroaryl group); (in the 5- to 7-membered saturated heterocyclic group, the 5- to 7-membered nitrogen-containing heterocyclic group and the 5- to 6-membered heteroaryl group in the above 2), 4), 5) and 7), a group having a cyclic secondary amine may be one wherein the amine is protected); and
n: 0, 1 or 2).
The compounds of the present invention are characterized by having a chemical structure in which a difluoro group is present on a ring carbon atom adjacent to an azepine ring carbon atom substituted with a (substituted) methylidene group. Since the compounds of the present invention have a difluoro group, they are not isomerized but have good stability even in vivo.
Preferred compounds of the present invention are those in which R1 is a group represented by the formula, NR3R4 wherein R3 and R4 are an optionally lower alkyl-substituted 5- to 7-membered saturated heterocyclic group or a 5- to 6-membered heteroaryl group, or the formula, NR3R4 may be integrated to form an optionally substituted 5- to 7-membered nitrogen-containing heterocyclic group. More preferred compounds are those in which R2 is an optionally halogen atom-substituted lower alkyl group.
The compounds (I) of the present invention will be further illustrated below. Unless otherwise mentioned in the definitions for the formula in this specification, the term xe2x80x9clowerxe2x80x9d means a carbon chain, either straight or branched, having from 1 to 6 carbon atoms. The xe2x80x9clower alkylene groupxe2x80x9d stands for an alkylene group having one to six carbon atoms, and its preferred examples are a methylene group, an ethylene group, a propylene group, a butylene group, etc.
The xe2x80x9c5-membered heteroarylene groupxe2x80x9d is a cyclic group where two linkages are available from a 5-membered monocyclic heteroaryl group, and specific examples thereof are furandiyl, thiophendiyl, pyrroldiyl, imidazoldiyl, thiazoldiyl, oxazoldiyl, pyrazoldiyl, isothiazoldiyl, isoxazoldiyl, oxadiazoldiyl, thiadiazoldiyl, triazoldiyl, tetrazoldiyl, etc. Preferred are furandiyl, thiophendiyl, imidazoldiyl, thiazoldiyl, oxazoldiyl, pyrazoldiyl, isoxazoldiyl, and triazoldiyl, with thiazoldiyl, imidazoldiyl, and pyrazoldiyl being particularly preferred.
With regard to the xe2x80x9ccycloalkyl groupxe2x80x9d, those having 3 to 8 carbon atoms are preferred, and specific examples thereof are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.
With respect to the xe2x80x9caryl groupxe2x80x9d, those having 6 to 14 carbon atoms are preferred, and specific examples thereof are phenyl, tolyl, xylyl, biphenyl, naphthyl, indenyl, anthryl, phenanthryl, etc. Preferred are phenyl and naphthyl, with phenyl being particularly preferred.
Examples of the substituent in the xe2x80x9coptionally substituted aryl groupxe2x80x9d are a halogen atom, an optionally halogen atom-substituted lower alkyl, OH, a lower alkoxy, a lower alkanoyl, nitro, cyano, and amino, etc.
With respect to the xe2x80x9c5- to 6-membered heteroaryl groupxe2x80x9d, its specific examples are 5-membered heteroaryls such as furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, etc.; 6-membered heteroaryls such as pyridyl, pyrimidyl, pyridazinyl, pyrazyl, triazyl, etc.; and the like.
With respect to the xe2x80x9clower alkyl groupxe2x80x9d, its specific examples are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, etc. Preferred are alkyls having 1 to 4 carbon atoms, with methyl, ethyl, propyl, and isopropyl being particularly preferred.
The xe2x80x9chalogen atomxe2x80x9d means a fluorine atom, a chlorine atom, bromine atom, or an iodine atom.
The xe2x80x9coptionally halogen atom-substituted lower alkyl groupxe2x80x9d means an unsubstituted lower alkyl group or a group wherein one or more hydrogen atoms of a lower alkyl group are substituted with a halogen atom. Specific examples of the halogen atom-substituted lower alkyl group are fluoromethyl, chloromethyl, bromomethyl, iodomethyl, 1-chloroethyl, 2-chloroethyl, dichloromethyl, trifluoromethyl, dichlorobromomethyl, etc. Preferred is trifluoromethyl.
With respect to the xe2x80x9c5- to 7-membered saturated heterocyclic groupxe2x80x9d, its specific examples are pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholyl, thiomorpholyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, oxathiolanyl, azepanyl, diazepanyl, etc. Preferred are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and diazepanyl.
The expression of the xe2x80x9c5- to 7-membered nitrogen-containing heterocyclic group may be fused with a benzene ring or with a 5- to 6-membered heteroaryl groupxe2x80x9d means xe2x80x9ca 5- to 7-membered nitrogen-containing heterocyclic groupxe2x80x9d or xe2x80x9ca 5- to 7-membered nitrogen-containing heterocyclic group which is fused with a benzene ring or with a 5- to 6-membered heteroaryl groupxe2x80x9d, and specific examples of the xe2x80x9c5- to 7-membered nitrogen-containing heterocyclic groupxe2x80x9d are pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, azepanyl, morpholyl, thiomorpholyl, diazepanyl, etc. Preferred are piperidyl, piperazinyl, morpholyl, thiomorpholyl, and diazepanyl.
Specific examples of the xe2x80x9c5- to 7-membered nitrogen-containing heterocyclic group which is fused with a benzene ring or with a 5- to 6-membered heteroaryl groupxe2x80x9d are a nitrogen-containing saturated ring fused with a benzene ring, such as indolinyl, benzimidazolidinyl, benzopyrazodinyl, benzopiperidyl, benzopiperazinyl, benzazepinyl, etc.; a nitrogen-containing heterocyclic group fused with a 5- to 6-membered heteroaryl group, such as tetrahydronaphthylidinyl, tetrahydropyridoazepinyl, tetrahydroimidazopyridyl, tetrahydroimidazopyrimidyl, etc.; and the like. Preferred are tetrahydronaphthylidinyl, tetrahydropyridoazepinyl, and tetrahydroimidazopyridyl.
Examples of the substituent in the xe2x80x9coptionally substituted 5- to 7-membered nitrogen-containing heterocyclic group formed by integration of NR3R4xe2x80x9d are (1) oxo, (2) OH, (3) a lower alkylidene (the lower alkylidene may be substituted with carbamoyl, carboxyl, or a lower alkoxycarbonyl), (4) a lower alkoxy (the lower alkoxy may be substituted with a lower alkoxycarbonyl or carboxyl), (5) carboxyl, (6) a lower alkoxycarbonyl, (7) carbamoyl (the carbamoyl group may be substituted with a lower alkyl which may be substituted with a lower alkoxycarbonyl or carboxyl, or a lower alkoxy), (8) a lower alkanoyl (the lower alkanoyl may be substituted with a lower alkoxycarbonyl or carboxyl), (9) amino (the amino may be substituted with or protected by a lower alkyl which may be substituted with a lower alkoxycarbonyl, a lower carbamoyl or carboxyl, or a lower alkanoyl which may be substituted with a lower alkoxycarbonyl or carboxyl), (10) imino (the imino may be substituted with OH, an optionally substituted lower alkoxy, a lower alkanoyloxy, or a lower alkanoyloxy which may be substituted with an optionally lower alkyl-substituted amino; and examples of the substituent in the optionally substituted lower alkoxy are a lower alkoxycarbonyl, carboxyl, a lower carbamoyl which may be substituted with an optionally lower alkoxy-substituted aminoalkyl, a saturated heterocycle, an optionally protected heteroaryl, etc.), (11) an optionally lower alkyl-substituted aryl, (12) a heteroaryl, (13) morpholyl, (14) a cycloalkyl, (15) an optionally lower alkanoyl-substituted hydrazone, (16) an optionally substituted hydrazino, (17) a lower alkenyl which may be substituted with a lower alkoxycarbonyl or carboxyl, (18) a lower alkyl (the lower alkyl may be substituted with OH, an optionally OH-substituted lower alkoxy (the lower alkoxy may be substituted with a lower alkoxycarbonyl or carboxyl), carboxyl, a lower alkoxycarbonyl, carbamoyl (the carbamoyl may be substituted with an optionally substituted lower alkyl; and examples of the substituent in the optionally substituted alkyl are a lower alkoxycarbonyl, carboxyl, an optionally lower alkyl-substituted amino, etc.), cyano, amino (the amino may be substituted with or protected by a lower alkyl), morpholyl, a lower alkanoyloxy, an optionally OH-substituted imino, or an optionally substituted or protected heteroaryl), etc. Preferred are (1) OH, (2) carbamoyl, (3) carboxyl, (4) amino (the amino may be substituted with a lower alkyl or a lower alkanoyl), (5) oxo, (6) imino (the imino may be substituted with OH, a lower alkoxy, a lower alkanoyloxy, or an optionally carboxyl-substituted lower alkoxy), (7) an optionally lower alkoxycarbonyl-substituted lower alkanoyl, (8) an optionally carboxyl-substituted lower alkoxy, (9) an optionally carboxyl-substituted lower alkenyl, (10) an optionally lower alkanoyl-substituted hydrazone, and (11) a lower alkyl (the lower alkyl group which may be substituted with OH, a lower alkoxy, a lower alkoxycarbonyl, amino (the amino may be substituted with a lower alkyl), carboxyl or carbamoyl).
The protective group for the xe2x80x9coptionally protected amino groupxe2x80x9d or the xe2x80x9coptionally protected mono-lower alkylamino groupxe2x80x9d and the protective group in an expression of xe2x80x9cin a group having a cyclic secondary amine, the amine may be protectedxe2x80x9d each means a protective group for the amino group which is usually used by those persons skilled in the art, and representative examples thereof are acyls such as formyl, acetyl, trifluoroacetyl, propionyl, methoxyacetyl, meth-oxypropionyl, benzoyl, thienylacetyl, thiazolylacetyl, tetrazolylacetyl, thiazolylglyoxyloyl, thienylglyoxyloyl, etc.; lower alkoxycarbonyls such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.; aralkyloxy-carbonyls such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.; lower alkanesulfonyls such as methanesulfonyl, ethanesulfonyl, etc.; aralkyls such as tosyl, benzyl, p-nitrobenzyl, benzhydryl, trityl, etc.; tri-lower alkylsilyls such as trimethylsilyl, etc.; and the like.
The compound of the present invention can form a salt, and examples of the acid addition salt are those with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; those with organic acids such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, citric acid, malic acid, tartaric acid, carbonic acid, methanesulfonic acid, ethanesulfonic acid, glutamic acid, aspartic acid, etc.; and the like. Examples of the base addition salt are salts with inorganic bases of sodium, potassium, magnesium, calcium, aluminum, etc., organic bases such as methylamine, ethylamine, ethanolamine, ammonia, etc.; bases of basic amino acids such as lysine, ornithine, etc.; and the like.
In the compound of the present invention, there are tautomers due to conjugated double bonds, and with regard to a substituted methylidene group bound to a benzazepine ring, a (Z)-isomer is preferred. Depending upon the type of the substituent of the compound of the present invention, optical isomers due to the presence of asymmetric carbon atoms, or isomers due to the presence of a hydroxyimino group, a lower alkoxyimino group, or a lower alkanoyloxyimino group, can be present. The present invention includes all of these isomers in a form of both separated and mixed ones.
Depending upon the physicochemical properties or manufacturing conditions, the compound of the present invention can be isolated as a hydrate, as a solvate with ethanol, etc. or as a substance having various crystalline forms giving crystalline polymorphism, and the present invention includes all of these hydrates, solvates with ethanol, etc. and substances in various crystalline forms.
(Manufacturing Methods)
The compound (I) of the present invention can be manufactured by applying various synthetic methods utilizing the characteristics due to its fundamental skeleton or to the type of the substituent. Representative manufacturing methods are given hereunder.
Incidentally, it is also possible in the synthesis that the functional group of the starting material or of the compound of the present invention is provided for a reaction after protecting with a suitable protective group. Examples of such a protecting group are those which are mentioned, for example, in Greene and Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d (second edition), and they can be appropriately used depending upon the reaction conditions. In the case of an aldehyde, it can be reacted as an acetal, followed by returning to an aldehyde group.
First Manufacturing Method 
(In the formulae, ring A, ring B, R2 and n have the same meanings as defined before; and R5 is a protective group for hydroxyl group.)
This manufacturing method is a method wherein a benzoazepine compound of formula (IIa) is reacted with a carboxylic acid of formula (III) or a reactive derivative thereof to conduct an amidation reaction, whereby a compound (Ia) of the present invention is synthesized, followed by hydrolyzing to give a compound (Ib) of the present invention.
Examples of the reactive derivative of the compound (III) are conventionally used usual esters such as methyl ester, ethyl ester, isobutyl ester, tert-butyl ester, etc. of carboxylic acid; acid halides such as acid chloride or acid bromide; acid azides; active esters which are obtained by the reaction with a phenolic compound such as 2,4-dinitrophenol, etc. or with an N-hydroxylamine-based compound such as 1-hydroxysuccinic acid imide, 1-hydroxybenzotriazole, etc.; symmetric acid anhydrides; mixed anhydrides such as organic acid-based mixed acid anhydrides which are obtained by the reaction with a halogenocarboxylic acid alkyl ester such as alkyl carbonate halides, etc. or with a pivaloyl halide, and phosphoric acid-based mixed acid anhydrides which are obtained by the reaction with diphenyl chloride phosphoryl or N-methylmorpholine; and the like.
When a carboxylic acid is reacted in a form of free acid or without isolation of the active ester, it is preferred to use a condensing agent such as dicyclohexylcarbodiimide (DCC), 1,1xe2x80x2-carbonyldimidazole (CDI), diphenyl phosphoryl azide (DPPA), diethyl phosphoryl cyanide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl), etc.
In particular, in the present invention, an acid chloride method, a method where the reaction is conducted in the presence of an active esterifying agent and a condensing agent, and a method where a usual ester is subjected to a treatment with an amine are convenient since they give the compound of the present invention in an easy and simple manner.
The reaction is usually conducted in an organic solvent which is inert to the reaction, such as halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ethers such as diethyl ether, tetrahydrofuran, etc.; esters such as ethyl acetate, etc.; N,N-dimethylformamide; dimethyl sulfoxide; etc. with cooling, with cooling to ambient temperature, or at ambient temperature to heating, depending upon the type of the reactive derivatives used, although such can vary depending upon the reactive derivative and condensing agent used for the reaction, etc.
In conducting the reaction, it is sometimes advantageous for proceeding the reaction smoothly to use the benzazepine compound (IIa) excessively or to conduct the reaction in the presence of a base such as N-methylmorpholine, trimethylamine, triethylamine, N,N-dimethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, picoline, lutidine, etc. Pyridine can be used as a solvent as well.
In the reaction where the compound (Ia) is hydrolyzed to synthesize the compound (Ib), the hydrolysis is conducted with cooling, with cooling to at ambient temperature, or at ambient temperature to heating, in the presence of a suitable catalyst such as acids or bases in the above-mentioned inert solvent or in a mixed solvent of water with an alcoholic solvent such as methanol, ethanol, etc.
The protective group R5 for the hydroxyl group means a protective group for hydroxyl group which is usually used by those persons skilled in the art, and its representative examples are lower alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group, etc.; lower alkyl groups where the arbitrary hydrogen atom or atoms of the above lower alkyl group are substituted with a lower alkoxy group; lower alkoxy-lower alkoxy-lower alkyl groups; aryl methyl groups such as benzyl group, etc.; acyl groups such as benzoyl group, a lower alkanoyl group; etc.; and the like. 
(In the formulae, ring A, ring B, R2, R3 and R4 and n have the same meanings as defined already.)
This manufacturing method is a method for the manufacture of a compound (Ic) of the present invention by the reaction of the compound (Ib) with an amine of the formula (IV). The reaction conditions for this step are the same as those given for the amidation reaction shown in the first step of the first manufacturing method.
Second Manufacturing Method 
(In the formulae, R3 and R4 have the same meanings as defined already, and R6 is a hydrogen atom or a protective group.)
This manufacturing method is a method where a compound (IIb) is reacted with an amine of the formula (IV) to give a compound (IIc). The reaction conditions for this step are the same as those mentioned for the amidation reaction given in the first step of the first manufacturing method.
In particular, in the present invention, a method where the reaction is conducted in the presence of both an active esterifying agent and a condensing agent, and a method where a usual ester is treated with an amine are simple and easy. When R6 is a protective group, it can be subsequently removed by conventional means, if desired, to prepare (IId). 
(In the formulae, ring A, ring B, R2, R3, R4 and n have the same meanings as defined already.)
This manufacturing method is a method where a compound (IId) is reacted with a carboxylic acid of the formula (III) or a reactive derivative thereof to give the compound (Ic) of the present invention. The reaction conditions for this step are the same as those in the amidation reaction shown in the first step of the first manufacturing method.
An acid chloride method is particularly convenient and easy in the present invention.
Third Manufacturing Method 
(In the formulae, ring A, ring B, R2 and n have the same meanings as defined already.)
This manufacturing method is a method in which the compound (Ib) is esterified, followed by subjecting to reduction to give a compound (Id) of the present invention.
The esterification reaction is conducted using an N-hydroxyamine-based compound such as 1-hydroxysuccinimide, etc. in the presence of the condensing agent mentioned in the first step of the first manufacturing method while stirring in the above-mentioned inert solvent with cooling, with cooling to at room temperature, or at room temperature to heating (under refluxing).
The reduction reaction is conducted using a reducing agent (such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, aluminum diisobutyl hydride, etc.) in an alcohol or in the above-mentioned inert solvent with cooling, with cooling to at room temperature, or at room temperature to heating (under refluxing). 
(In the formulae, ring A, ring B, R2, R3, R4 and n have the same meanings as defined already.)
This manufacturing method is a method in which the compound (Id) is sulfonated, followed by subjecting to a reaction with the amine represented by the formula (IV) to give a compound (Ie) of the present invention.
The sulfonation reaction is conducted by a sulfonating reagent such as tosylic acid halides, methanesulfonic acid halides, etc. in the presence of the above-mentioned inert solvent with cooling, with cooling to at room temperature, or at room temperature to heating (with refluxing) with stirring. It is also possible to add a base (such as inorganic bases, e.g., potassium carbonate, sodium carbonate, etc., or organic bases, e.g., triethylamine, etc.) to promote the reaction.
The amination reaction is conducted in the above-mentioned inert solvent with cooling, with cooling to at room temperature, or at room temperature to heating (under refluxing) with stirring. It is also possible to add sodium iodide, potassium iodide, etc. to promote the reaction.
(Other Manufacturing Methods)
In addition to the above-mentioned methods, the compounds of the present invention can be manufactured by conversion of various substituents. For example, in the case of the compounds of formula, NR3R4, wherein R3 and R4 are an alkyl group-based substituent, or R3 and R4are taken together to form an optionally substituted 5- to 7-membered nitrogen-containing hetero-cyclic group having a substituent at the nitrogen atom in the heterocyclic group, a conventional N-alkylating reaction by the reaction of the corresponding alkyl halide or alkyl sulfonate compound with the corresponding amine is conducted. Specifically, an alkyl halide or alkyl sulfonate compound and the amine in an amount corresponding to the reaction are stirred in the above-mentioned inert solvent with cooling, with cooling to at room temperature, or at room temperature to heating (under refluxing). It is also possible to add a base (such as inorganic bases, e.g., potassium carbonate, sodium carbonate, etc., and organic bases, e.g., triethylamine, etc.) to promote the reaction.
In the case of aromactic amino compounds, they can be manufactured by reducing the corresponding nitro compounds by conventional means. In the case of compounds substituted with a lower alkyl group, they can be manufactured by applying the conventional method mentioned for the above N-alkylation while, in the case of compounds having a saturated ring, they can be manufactured by applying the above N-alkylation using the corresponding dihalides.
Compounds having an amine structure at the end, they can be manufactured from the corresponding compounds having a hydroxyl group by an amination reaction mentioned in the above second step of the third manufacturing method. Compounds having a hydroxime or alkoxime structure at the end can be manufactured by conventional means, wherein the corresponding compound having a carbonyl group is condensed with hydroxylamine or with an alkoxylamine. Further, acyloxyimino compounds can be manufactured by subjecting the corresponding hydroxime compound to conventional acylation. In addition, the compounds having an acetylpiperidino group in NR3R4 can be manufactured from the corresponding N-methoxy-N-methyl-carbamoyl-substituted compound having a piperidino group.
In removing the protective group from the xe2x80x9coptionally protected amino groupxe2x80x9d or the xe2x80x9coptionally protected mono-lower alkylamino groupxe2x80x9d and the protective group from the case where xe2x80x9cin a group having a cyclic secondary amine, the amine may be protectedxe2x80x9d, the conventional methods mentioned in the above-mentioned references such as that by Greene, et al. can be used. Also, compounds having a hydrazone structure or an ether structure at the end can be manufactured by usual hydrazonation reaction or O-alkylation reaction.
The compound of the present invention manufactured as such can be isolated and purified as it is or as a salt thereof after subjecting to a salt formation process by conventional means. The isolation and purification can be conducted by applying usual chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various chromatographic means, etc.
Each of the isomers can be isolated by usual methods utilizing the difference in physicochemical properties among the isomers. For example, in the case of racemic compounds, a sterically pure isomer can be prepared by means of usual racemic resolution [e.g., diastereomer salts with a usual optically active acid (such as tartaric acid, etc.) are prepared, followed by subjecting to optical resolution, etc.]. In the case of a mixture of diastereomers, they can be separated, for example, by means of fractional crystallization, chromatography, etc. It is also possible to manufacture an optically active compound starting from an appropriate optically active material.
Industrial Applicability
4,4-Difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepine derivatives which are represented by the formula (I) and salts thereof according to the present invention have an antagonistic action to oxytocin and therefore, are useful as remedies for inhibiting threatened premature birth or abortion, or precesarean birth, dysmenorrhea, suppression of contraction of uterine smooth muscle, suppression of release of milk, etc. In addition, due to their nature as an oxytocin antagonist may be also applicable to endometriosis (Adv. Exp. Med. Biol., 395: 491-493, 1995), feeding control (Neruosci. Biobehav. Rev., 15: 217-231, 1991), disturbance of memory (Eur. J. Pharmacol., 94: 125-131, 1983; J. Pharmacol. Exp. Ther., 241: 268-274, 1987), natriuresis (J. Pharmacol. Exp. Ther., 246: 603-609, 1988), carbohydrate metanolism regulation (Acta. Physiol. Scand., 144: 355-359, 1992), prostatic hypertrophy (Adp. Exp. Med. Biol., 395: 529-538, 1995), breast cancer (Endocrinology, 137: 773-779, 1996), etc. Moreover, in view of the investigations at present, they also participate in the functions such as regulation of ovulatory and luteal functions in ovarium (J. Reprod. Fert., 91: 49, 1991; J. Reprod. Fert., 90: 625, 1990), regulation of sperm transportation (Igaku Seirigaku Tenbo, a book, 14th edition, 1990), regulation of sexual behavior (J. Clin. Endocrinol. Metab., 64: 27, 1987; Neurosci. Biobehav. Rev., 16: 131-144, 1992), regulation of maternal behavior (Proc. Natl. Acad. Sci. USA, 89: 5981, 1992), etc. Effects of the compounds of the present invention have been ascertained by the following tests.
(Oxytocin Receptor Binding Assay)
Preparation of Uterine membrane was prepared by a method of Soroff, et al. (J. Biol. Chem., 249: 1376, 1974) while a binding assay was performed by a method of Pettibone, et al. (Endocrinology, 125: 217, 1989). Diethylstilbestrol dipropionate (0.3 mg/kg) was administered to a rat intraperitoneally, and after 18 to 24 hours, uterus was excised, and a membrane sample was prepared therefrom. [3H]-Oxytocin (0.5 nM; specific activity=30 to 60 Ci/mmol), 50 xcexcg of the membrane sample and a test drug (10xe2x88x928 to 10xe2x88x925 M) were incubated at room temperature for 60 minutes in 250 xcexcl (total volume) of 50 mM Tris hydrochloride buffer (pH 7.4) containing 10 mM of magnesium chloride and 0.1% of bovine serum albumin (BSA). After that, the incubated solution was sucked using a cell harvester and collected by filtration through a glass filter (GF/C) to remove a free ligand and an excessive buffer, and a labeled ligand bound to the receptor was trapped. The glass filter was taken out, well dried and mixed with a cocktail for liquid scintillation, the amount of [3H]-oxytocin bound to the sample was determined by a liquid scintillation counter, and the inhibition rate was calculated from the following equation:
Inhibition rate (%)=100xe2x88x92(C1xe2x88x92B1/C0xe2x88x92B1)xc3x97100
wherein
C1: The amount of [3H]-oxytocin binding to the membrane sample when a known amount of the test drug and [3H]-oxytocin coexisted and were treated with the membrane sample;
C0: The amount of [3H]-oxytocin binding to the membrane sample when there was no test drug, but [3H]-oxytocin and the membrane sample were treated with the membrane sample; and
B1: The amount of [3H]-oxytocin binding to the membrane sample when excessive oxytocin (10xe2x88x926 M), [3H]-oxytocin and the membrane sample were treated.
IC50 was determined from the concentration of the test drug when the inhibition rate calculated above became 50%, and then the affinity of binding of the nonradioactive ligand, that is, a dissociation constant (Ki), was calculated by the following equation:
Ki=IC50/(1+[L]/Kd)
wherein [L] is a concentration of the radioactive ligand; and Kd is a dissociation constant calculated from the scattered plots.
Then, a negative logarithmic value of Ki calculated hereinabove was taken as pKi. Accordingly, the more the pKi, the stronger the bound to oxytocin receptor.
From the above-mentioned test, it was ascertained that the compounds of the present invention strongly bond to the oxytocin receptor. For example, the compound of Example 4-2 showed a binding activity of as strong as where pKi was 8.90 in the oxytocin receptor binding test. The compound of Example 4-7 showed a pKi of 8.87, and the compound of Example 10-1 showed a pKi of 8.68. Incidentally, the pKi value of atosiban was 7.93.
Further, some compounds of the present invention showed a binding activity to V1 or V2 receptor.
A drug composition containing one or more of the compounds of the present invention or salts thereof is prepared using a usual pharmaceutically acceptable carrier. Administration of the drug composition in accordance with the present invention can be in any of oral administration and parenteral administration by means of, e.g., injections, suppositories, percutaneous agents, inhalants, intravesical infusions, etc.
Dose can be appropriately decided for each case by taking symptom, age/sex of the patient, etc. into consideration, but usually, it is around 0.01 mg/kg to 100 mg/kg per day for adults in the case of oral administration, and it is administered at one time or divided into two to four times a day. When intravenous injection is conducted depending upon the symptom, 0.001 mg/kg to 100 mg/kg at a time for adults is usually administered once or more times a day. Examples of the carrier for the preparation are solid or liquid nontoxic substances for drugs.
With respect to the solid composition for oral administration in accordance with the present invention, tablets, pills, capsules, powder, granules, etc. can be used. In such solid compositions, one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, agar, pectin, magnesium metasilicate aluminate and magnesium aluminate. The compositions can contain additives other than the inert diluent, such as lubricants, e.g., magnesium stearate, disintegrating agents, e.g., calcium cellulose glycolate, stabilizers, e.g., lactose, and auxiliary solubilizers, e.g., glutamic acid and aspartic acid, in accordance with a conventional means. Tablets or pills can be coated, if necessary, with sugar coat such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, etc., or with a film made of a substance which is soluble in gastric juice or intestinal juice.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixiers, etc. and contain usually used inert diluents such as purified water and ethanol. In addition to the inert diluents, the compositions can further contain auxiliary agents such as moisturizers or suspending agents, sweeteners, tasting agents, aromatic agents, and antiseptics.
Injections for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline solution. Examples of nonaqueous solutions and suspensions are propylene glycol, polyethylene glycol, vegetable oils such as cacao butter, olive oil and sesame oil, alcohols such as ethanol, gum arabic, Polysolvate 80 (a trade name), etc. These compositions can further contain auxiliary agents such as isotonizing agents, antiseptics, moisturizers, emulsifiers, dispersing agents, stabilizers (e.g., lactose) and auxiliary solubilizers (e.g., glutamic acid and aspartic acid). These can be sterilized, for example, by filtration passing through a bacteria preserving filter, compounding with a bactericide or irradiation. These can also be used by manufacturing a sterile solid composition, followed by dissolving in sterile water or a sterile solvent for injection before use.
The present invention is further illustrated by way of the following Examples. Compounds of the present invention are not limited to those which are mentioned in the following Examples only but they include all of the compounds represented by the above-mentioned formula (I) as well as salts, hydrates, geometric and optical isomers and crystalline polymorphism thereof. Furthermore, when the materials used in the present invention are novel, they are mentioned in the Referential Examples as hereunder.
(Table 1)
To 60 ml of a methanolic solution of 2.27 g of methyl (Z)-(4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene)acetate was added 30 ml of a 1N aqueous solution of sodium hydroxide, and the mixture was stirred at room temperature for 18 hours. To the reaction solution was added 30 ml of 1N hydrochloric acid, and the solvent was evaporated therefrom. To the residue were added 30 ml of acetonitrile, 1.82 g of 1-hydroxybenzotriazole, 2.59 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride and 1.76 g of 4-(2-aminoethyl)morpholine, and the mixture was stirred at room temperature for 18 hours. After evaporation of the solvent, ethyl acetate was added to the residue, and the mixture was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of NaCl. This was dried over magnesium sulfate, and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (eluting with ethyl acetate-methanol). The resulting residue was crystallized from diethyl ether to give 2.06 g of (Z)-(4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene)-N-(2-morpholinoethyl)acetamide as a colorless powder.
(Table 1)
To a solution of 10 g of (Z)-(4,4-difluoro-1-tosyl-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene)acetic acid in 100 ml of tetrahydrofuran were added 4.12 g of 1-hydroxybenzotriazole, 5.85 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride and 3.36 ml of 1-methylpiperazine, followed by stirring for two hours at room temperature. After evaporation of the solvent, ethyl acetate was added to the residue, and the mixture was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of NaCl. After drying over magnesium sulfate, the solvent was evaporated off. The resulting residue was collected by filtration to give 11.76 g of (Z)-4,4-difluoro-5-[2-(4-methylpiperazin-1-yl)-2-oxoethylidene]-1-tosyl-2,3,4,5-tetrahydro-1H-1-benzoazepine as a colorless amorphous solid.
(Table 1)
(Z)-4,4-Difluoro-5-[2-(4-methylpiperazin-1-yl)-2-oxoethylidene]-1-tosyl-2,3,4,5-tetrahydro-1H-1-benzoazepine (11.7 g) was dissolved in 20 ml of concentrated sulfuric acid, followed by stirring for 24 hours at room temperature. The reaction solution was poured over 700 ml of a 1N aqueous solution of sodium hydroxide and extracted with chloroform. The organic layer was washed with a saturated aqueous solution of NaCl, and after drying over magnesium sulfate, the solvent was evaporated off. The resulting residue was crystallized from diethyl ether to give 7.62 g of (Z)-4,4-difluoro-5-[2-(4-methylpiperazin-1-yl)-2-oxoethylidene]-2,3,4,5-tetrahydro-1H-1-benzoazepine as a colorless powder.